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A Phase I Clinical Trial to Assess Safety and Tolerability of Injectable Collagenase in Women with Symptomatic Uterine Fibroids.

ABSTRACT: Uterine fibroids feature excessive deposition of types I and III collagen. Previous ex vivo studies showed an FDA-approved collagenase (EN3835)-digested types I and III collagen fibers in fibroid tissues; however, collagenase had not been evaluated in vivo for effects on uterine fibroids. The objective was to assess the safety and tolerability of collagenase injection directly into uterine fibroids. This was a prospective, open label, dose escalation study. The study participants were fifteen women aged 35-50 years with symptomatic uterine fibroids planning to undergo hysterectomy. Three subjects received saline and methylene blue, three subjects received a fixed dose of EN3835, and 9 subjects received stepped, increasing dosages of EN3835, all by transvaginal, ultrasound-guided injections. Primary outcome measures were safety and tolerability of the injection and change in collagen content between treated and control tissues. There were no significant adverse events following injection of EN3835 into uterine fibroids. Masson's trichrome stains revealed a 39% reduction in collagen content in treated samples compared to controls (p <0.05). Second harmonic generation (SHG) analysis showed treated samples to have a 21% reduction in density of collagen compared to controls. Picrosirius-stained collagenase-treated fibroids showed collagen fibers to be shorter and less dense compared to controls. Subjects reported a decrease in fibroid-related pain on the McGill Pain Questionnaire after study drug injection in Group 2 at both 4-8 days and 60-90 days post-injection. The findings indicated that injection of collagenase was safe and well tolerated. These results support further clinical investigation of collagenase as a minimally invasive treatment of uterine fibroids. NCT0289848.

SUBMITTER: Singh B

PROVIDER: S-EPMC8346429 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThis study evaluated treatment patterns among women diagnosed with symptomatic uterine fibroids (UF) in the United States. Data were retrospectively extracted from the IBM Watson Health MarketScan® Commercial Claims and Encounters and Medicaid Multi-State databases.MethodsWomen aged 18-64 years with ≥1 medical claim with a UF diagnosis (primary position, or secondary position plus ≥1 associated symptom) from January 2010 to June 2015 (Commercial) and January 2009 to December 2014 (Medicaid) were eligible; the first UF claim during these time periods was designated the index date. Data collected 12 months pre- and 12 and 60 months post-diagnosis included clinical/demographic characteristics, pharmacologic/surgical treatments, and surgical complications. Prevalence (2015) and cumulative incidence (Commercial, 2010-2015; Medicaid, 2009-2015) of symptomatic UF were estimated.Results225,737 (Commercial) and 19,062 (Medicaid) women had a minimum of 12 months post-index continuous enrollment and were eligible for study. Symptomatic UF prevalence and cumulative incidence were: 0.57, 1.23% (Commercial) and 0.46, 0.64% (Medicaid). Initial treatments within 12 months post-diagnosis were surgical (Commercial, 36.7%; Medicaid, 28.7%), pharmacologic (31.7%; 53.0%), or none (31.6%; 18.3%). Pharmacologic treatments were most commonly non-steroidal anti-inflammatory drugs and oral contraceptives; hysterectomy was the most common surgical treatment. Of procedures of abdominal hysterectomy, abdominal myomectomy, uterine artery embolization, and ablation in the first 12 months post-index, 14.9% (Commercial) and 24.9% (Medicaid) resulted in a treatment-associated complication. Abdominal hysterectomy had the highest complication rates (Commercial, 18.5%; Medicaid, 31.0%).ConclusionsOff-label use of pharmacologic therapies and hysterectomy for treatment of symptomatic UF suggests a need for indicated non-invasive treatments for symptomatic UF.

Project description:BackgroundThere are no proven therapies that modify the structural changes associated with osteoarthritis (OA). Preclinical data suggests that intra-articular recombinant human BMP-7 (bone morphogenetic protein-7) has reparative effects on cartilage, as well as on symptoms of joint pain. The objective of this study was to determine the safety and tolerability as well as dose-limiting toxicity and maximal tolerated dose of intra-articular BMP-7. The secondary objectives were to determine the effect on symptomatic responses through 24 weeks.MethodsThis was a Phase 1, double-blind, randomized, multi-center, placebo-controlled, single-dose escalation safety study consisting of 4 dosing cohorts in participants with knee OA. Each cohort was to consist of 8 treated participants, with treatment allocation in a 3:1 active (intra-articular BMP-7) to placebo ratio. Eligible participants were persons with symptomatic radiographic knee OA over the age of 40. The primary objective of this study was to determine the safety and tolerability of BMP-7 including laboratory assessments, immunogenicity data and radiographic assessments. Secondary objectives were to determine the proportion of participants with a 20%, 50%, and 70% improvement in the WOMAC pain and function subscales at 4, 8, 12, and 24 weeks. Other secondary outcomes included the change from baseline to 4, 8, 12, and 24 weeks for the OARSI responder criteria.ResultsThe mean age of participants was 60 years and 73% were female. All 33 participants who were enrolled completed the study and most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. The 1 mg BMP-7 group showed a higher frequency of injection site pain and there was no ectopic bone formation seen on plain x-rays. By week 12, most participants in both the BMP-7 and placebo groups experienced a 20% improvement in pain and overall the BMP-7 group was similar to placebo with regard to this measurement. In the participants who received 0.1 mg and 0.3 mg BMP-7, there was a trend toward greater symptomatic improvement than placebo. The other secondary endpoints showed similar trends including the OARSI responder criteria for which the BMP-7 groups had more responders than placebo.ConclusionsThere was no dose limiting toxicity identified in this study. The suggestion of a symptom response, together with the lack of dose limiting toxicity provide further support for the continued development of this product for the treatment of osteoarthritis.

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A Phase I Clinical Trial to Assess Safety and Tolerability of Injectable Collagenase in Women with Symptomatic Uterine Fibroids.

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